Nadal looks to extend stranglehold over Gasquet at US Open
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The Spaniard is bidding to become the oldest champion in New York since Bill Tilden in 1929.
The 36-year-old is the star attraction on an Arthur Ashe Stadium which on Friday bid an emotional farewell to Serena Williams, who ended her career on 23 majors, one more than the 22 that Nadal currently possesses.
As well as losing 17 times in 17 meetings with Nadal on the professional circuit, the Frenchman has lost the last 31 sets against his childhood rival.
"We are both 36 years old, but in terms of recovery, we are not equal," said Gasquet.
"I'm going there to play a great match and you never know what can happen."
Nadal arrived at the US Open having played just one match since forfeiting his Wimbledon semi-final due to an abdominal injury.
In New York, he has dropped the opening set in both of his first two matches.
Against Fabio Fognini, he injured himself with his own racquet which bounced off the court and crashed into his nose.
Nadal has also admitted his concerns over his wife Mery Perello -- due to give birth to the couple's first child in the coming weeks.
Spanish media reports claimed she had been admitted to hospital as a precautionary measure.
"My wife is fine, but in the end these are situations that are sometimes more difficult to manage when you are away from home," said Nadal.
Meanwhile, fellow Spaniard Carlos Alcaraz, widely-regarded as Nadal's Grand Slam heir apparent, tackles Jenson Brooksby of the United States.
The 19-year-old Alcaraz has not dropped a set at the tournament where he reached the quarter-finals in 2021.
Alcaraz is bidding to become the youngest man to reach the US Open fourth round in back-to-back years since Pete Sampras more than 30 years ago.
World number 43 Brooksby made the last-16 in 2021.
In the women's draw, world number one and French Open champion Iga Swiatek seeks a second successive fourth round spot at the US Open when she faces unseeded Lauren Davis of the United States.
Swiatek has never lost to a player outside the top 100 at the Grand Slams.
Only five of the women's top 10 seeds remain in the tournament.
Sixth seed Aryna Sabalenka, who made the semi-finals in 2021, saved two match points in her second round win over Kaia Kanepi.
The Belarusian faces French qualifier Clara Burel, the 131st-ranked player who knocked out Wimbledon champion Elena Rybakina in the first round.
China's Yuan Yue is the second qualifier to make the last 32 and she takes on US eighth seed Jessica Pegula.
Fellow Chinese player Zheng Qinwen, who defeated former French Open champion Jelena Ostapenko in the first round, plays Germany's Jule Niemeier.
Big-serving Zheng, just 19, has hit a tournament-leading 32 aces so far, one more than the now retired Serena Williams.
Zhang Shuai has already reached the last 16 but there has never been more than one Chinese woman in the fourth round at the US Open.
In a battle of multiple Grand Slam champions, Garbine Muguruza meets Petra Kvitova for the sixth time.
Two-time Wimbledon champion Kvitova holds a 5-1 career lead over the Spaniard.